EP0229016B1 - Interleukin-2 compositions - Google Patents

Interleukin-2 compositions Download PDF

Info

Publication number
EP0229016B1
EP0229016B1 EP87100067A EP87100067A EP0229016B1 EP 0229016 B1 EP0229016 B1 EP 0229016B1 EP 87100067 A EP87100067 A EP 87100067A EP 87100067 A EP87100067 A EP 87100067A EP 0229016 B1 EP0229016 B1 EP 0229016B1
Authority
EP
European Patent Office
Prior art keywords
solution
acid
compositions
interleukin
freeze
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP87100067A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP0229016A3 (en
EP0229016A2 (en
Inventor
David R. Thatcher
Kazuhiro Shima
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shionogi and Co Ltd
Biogen MA Inc
Original Assignee
Shionogi and Co Ltd
Biogen NV
Biogen Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shionogi and Co Ltd, Biogen NV, Biogen Inc filed Critical Shionogi and Co Ltd
Priority to AT87100067T priority Critical patent/ATE82857T1/de
Publication of EP0229016A2 publication Critical patent/EP0229016A2/en
Publication of EP0229016A3 publication Critical patent/EP0229016A3/en
Application granted granted Critical
Publication of EP0229016B1 publication Critical patent/EP0229016B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2013—IL-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to interleukin-2 compositions very useful in medicine.
  • interleukin-2 compounds are a group of proteins with T cell growth activity, NK cell (natural killer cell) growth activity, or similar activity. They are regarded as promising agents in the treatment of various cancer or immunodeficiency diseases, and more recently of acquired immune deficiency syndrome (AIDS).
  • IL-2 interleukin-2 compounds
  • IL-2 compositions containing a reducing agent JP-A-60-215631
  • HSA human serum albumin
  • JP-A-60-222424 IL-2 compositions containing human serum albumin
  • WO-A-8 504 328 discloses an interleukin-2 composition showing a pH of 6.1 to 9 in a state of solution and further comprising mannitol and SDS.
  • the present invention provides IL-2 compositions containing serum albumin and showing a pH of 6.1 to 9 in a state of solution, which are prepared by adjusting a solution of IL-2 to pH 8 - 11, more preferably pH 9 - 11 with a base and immediately thereafter to pH 6.1 - 9 with an acid; or by adjusting a solution of IL-2 to pH 2 - 6, more preferably pH 2 - 4 with an acid and immediately thereafter to pH 6.1 - 9 with a base.
  • IL-2 compounds are slightly soluble in water, especially in a near neutral condition, and their solubility is greatly decreased because of their aggregation at the isoelectric point (pH about 7.6). It has therefore been quite difficult to prepare neutral compositions of IL-2 because of problems in the preparation of freeze-dried compositions and the poor solubility of such compositions when reconstituted for practical use.
  • compositions are preferably prepared so as to be in a physiologically acceptable pH range, considering that they are injected intraarterially, intravenously, intramuscularly, subcutaneously or intracutaneously. It is presumed, for instance, that an acidic composition often irritates the injected site and may cause undesired topical reactions such as local pain or inflammation at the injected site. In order to avoid such undesired effects the present inventors have conducted research into new compositions and succeeded in preparing IL-2 compositions of the present invention which are adjusted at a pH value which is in the physiological range.
  • compositions of the present invention exhibit excellent IL-2 stability in respect of the solution before freeze-drying and the freeze-dried compositions during preservation, in terms of the appearance and stability of the reconstituted solution, and in related aspects.
  • the present invention provides IL-2 compositions containing serum albumin (SA) and showing pH 6.1 - 9 in a state of solution, which are prepared by first adjusting a solution of IL-2 to pH 8 - 11, more preferably 9 - 11 and most preferably 9.5 - 10.5 with a base, and then immediately neutralizing it with an acid; or by adjusting said solution to pH 2 - 6, more preferably 2 - 4 and most preferably 2 - 3 with an acid, and then immediately neutralizing it with a base; and finally adjusting the solution so as to show pH 6.1 - 9, more preferably pH 6.1 - 8 and most preferably pH 6.5 - 7.5.
  • SA serum albumin
  • Any natural IL-2 can be used in this invention, and in addition recombinant human IL-2 is most preferably used.
  • IL-2 activity was assayed in the following manner in this invention: IL-2 activity was assayed by determining the 3H-thymidine incorporation of CTLL-2 (IL-2 dependent murine cell line). The units of the IL-2 activity were determined as a reciprocal of the dilution at which 50% of the maximum counts per minute was observed, and were corrected in Jurkat Unit (hereinafter abbreviated to JU) using BRMP standard [Lot No. ISDP-841: obtained from the National Cancer Institute (NCI)] of Jurkat-derived IL-2 (Jurkat: human T cell leukaemia cell line). In the following Examples IL-2 having a specific activity of (1.4 ⁇ 0.2)x107 JU/mg was employed, unless otherwise mentioned.
  • SA means serum albumin derived from a warm-blooded animal, including bovine serum albumin (hereinafter abbreviated to BSA), porcine serum albumin (PSA) and human serum albumin (HSA), from which a preferred one may be chosen according to the purpose.
  • BSA bovine serum albumin
  • PSA porcine serum albumin
  • HSA human serum albumin
  • Addition of SA is useful in avoiding a decrease in IL-2 activity or in preventing IL-2 from being adsorbed onto the inner walls of vessels.
  • SA may be used in 1 - 500 parts by weight, more preferably 10 - 200 parts by weight per 1 part of IL-2.
  • any kind of base can be employed as long as it is physiologically acceptable: as preferred examples alcoholamines such as N-methylglucamine, monoethanolamine, diethanolamine, and triethanolamine; alkylamines such as mono-, di-, and triethylamine; basic amino acids such as arginine, lysine, and histidine; inorganic bases such as sodium carbonate may be mentioned, and they may be used individually or as a mixture. In particular, N-methylglucamine, diethanolamine, triethanolamine, and arginine are preferred, being used individually or in combination. When an inorganic base is employed, it is appropriate to use in addition an amine or amide.
  • the amount of base so used varies with the kind of base, but they may be generally used in 10 - 500 parts by weight, more preferably 50 - 200 parts by weight, per 1 part of IL-2.
  • any kind of acid may be employed as long as it is physiologically acceptable.
  • organic acids such as acetic acid, lactic acid, succinic acid, tartaric acid and citric acid; and inorganic acids such as hydrochloric acid and phoshoric acid may be mentioned.
  • physiologically acceptable salts may be used individually or in combination.
  • Citric acid and tartaric acid are especially recommended.
  • the amount of acid so used varies with the type of acid, they may be used in the amount needed to adjust the composition to a desirable pH value. They are generally used in an amount of 5 -250 parts by weight, more preferably 20 - 100 parts by weight, per 1 part of IL-2.
  • sugars or sugar alcohols as the stabilizer or solubilizer for IL-2, or excipient.
  • Sugar means monosaccharides, polysaccharides, or water-soluble glucans including fructose, glucose, mannose, sorbose, xylose, maltose, lactose, sucrose, dextran, pullulan, dextrin, cyclodextrin, soluble starch, hydroxyethyl starch and carboxymethylcellulose-Na. Of all these, maltose is the most preferred.
  • Sugar alcohol mean C4-C8 and includes mannitol, sorbitol, inositol, dulucitol, xylitol and arabitol.
  • mannitol is the most preferred.
  • the sugars or sugar alcohols mentioned above may be used individually or in combination. There is no fixed limit to the amount used, as long as it is soluble in the aqueous preparation. In practice they are used in an amount of 10 to 100 mg/ml.
  • a buffer in order to minimize pH changes to the solution during the preparation steps or to the reconstituted solution.
  • Any physiologically acceptable buffer can be used in this invention, and an amount of the buffer as necessary may be used to keep the solution at a desirable pH value.
  • phosphate-type or citrate-type buffers may be used.
  • Surfactants may be added to the solution.
  • the addition of surfactants has a beneficial effect on the compositions of this invention, for example giving clearer solutions during preparation or on reconstitution, as well as lowering the adsorption rate of IL-2 onto the walls of vessels.
  • Non-ionic surfactants are especially preferred for this purpose, e.g. polyoxyethylene (POE), hydrogenated castor oils, polyethylene glycols (PEG) including PEG300 and PEG400 and, polyoxyethylene sorbitan aliphatic esters. They are used in an amount of 0.1 mg to 1 mg per millilitre of the aqueous preparation.
  • compositions of this invention An example of the preparation of the compositions of this invention is given below: To a solution of HSA and maltose dissolved in distilled water is added IL-2, with a surfactant if desired. The solution thus prepared is adjusted to a pH of about 10 with diethanolamine, combined with a buffer, and then immediately adjusted to a pH of about 7 with citric acid. An appropriate amount of distilled water is added thereto to make a suitable quantity of the solution, which is then aseptically filtered, distributed into vials, and freeze-dried. In the foregoing procedures the entire amount of HSA may be used at once in one portion; or it may be divided into two portions and one may be added first and the other after adjusting to a pH of about 7.
  • IL-2 is kept stable, and the solutions are also kept clear during preparation and after reconstitution. Accordingly, there is no upper limit to the final pH value in this invention, but it would be at pH 6.1 - 9 for the preferred compositions.
  • the compositions are preferably adjusted to a physiological pH value or thereabouts if they are intended as injections. In such a case the final pH value would be between 6.1 and 8, more preferably between 6.5 and 7.5. In an acidic range below the lowest limit mentioned above it is difficult to keep the appearance of the reconstituted solution clear.
  • An IL-2 composition thus prepared as an aqueous solution can be used just as it is, but it is preferably first converted into a freeze-dried formulation in the following manner: If a freeze-dried composition is needed, the following method would preferably be used: Said aqueous solution in a vessel is cooled and immediately frozen to a temperature of -60 to -10°C, more preferably -40 to -25°C; the water is removed from the frozen product by sublimation to a preset moisture content at a reduced pressure between 0.005 and 1 mb for a period of 5 - 72 hours, supplying the heat consumed by sublimation, if required. The vessel is further filled with an inert gas such as nitrogen, or with dry air, and tightly sealed if necessary.
  • an inert gas such as nitrogen, or with dry air
  • the present invention involves aqueous solutions as mentioned above, frozen or freeze-dried compositions of said solutions, and solutions of the freeze-dried compositions reconstituted in a suitable medium.
  • These compositions of the invention have advantages in that the loss of IL-2 during the preparation steps and preservation is very slight, and the decrease in specific activity of IL-2 is minimal.
  • the freeze-dried compositions have the significant advantage that the reconstituted solutions remain clear and adsorption of IL-2 onto the walls of the vessels is avoided.
  • the compositions of this invention very rarely irritate the parts of the body where they are administered because they are prepared in a physiological pH range, and as a result they very rarely produce undesired effects locally such as pain from injection, inflammation at the injection sites, or the like.
  • compositions of this invention are not limited in their route of application, but they may preferably be administered parenterally. When used as injections, they are administered intravenously, intramuscularly, subcutaneously or intracutaneously as a solution dissolved in distilled water, isotonic saline, or a suitable transfusion. As a matter of course, the compositions may be formulated into compositions for topical use such as an oral, nasal or otic administration together with a suitable carrier, excipient, or the like.
  • IL-2 if required with a surfactant.
  • the resulting solution is adjusted to pH 8-11 with a base, and then to pH 6.1-9 with an acid after or before addition of a surfactant.
  • the remaining amount of HSA, if any, is added thereto.
  • the resulting solution may be filtered under aseptic conditions to give a sterile solution which may he distributed into vials for injection.
  • IL-2 if required with a surfactant.
  • the resulting solution is adjusted to pH 2-6 with an acid, and then to pH 6.1-9 with a base after or before addition of a surfactant.
  • the remaining amount of HSA, if any, is added thereto.
  • the resulting solution may be filtered under aseptic conditions to give a sterile solution which may be distributed into vials for injection.
  • the above-prepared aqueous solution is rapidly cooled and frozen at -60 °C to -10 °C, preferably at -40 °C to -25 °C.
  • the water is removed by sublimation to a preset moisture content at a pressure of 0.005-1 mb for a period of 5-72 hours, if necessary supplying the heat of sublimation.
  • the vessel may be charged with an inert gas such as nitrogen or with dry air and sealed.
  • the solution thus prepared is filtered through an appropriate membrane filter to give a sterile solution, which is distributed into vials and frozen at a temperature below -35 °C.
  • the frozen composition is sublimated according to a conventional manner for freeze-drying, during which the composition placed in vials is kept at a temperature below -25°C, to give a freeze-dried composition.
  • the amount of each component summarized in Table 1 corresponds to that used for preparing 1.2 ml or 2 ml of the solutions.
  • the mark ⁇ means that the acid indicated by the mark is used in a calculated amount necessary to adjust the solution to the desirable pH value.
  • Composition (A) was prepared as a reference by adding IL-2 to a solution which is preliminarily adjusted to neutral pH using both base and acid.
  • a solution of 6.25 mg of HSA and 250 mg of maltose dissolved in 6.5 ml of distilled water for injection is adjusted to a pH of about 10.5 with 27 mg of diethanolamine, and then after addition of 1.25 ml of 0.2 M sodium phosphate buffer (pH 6.9) to a pH of about 7.0 with 0.16 ml of 10% citric acid. Then 6.25 mg of HSA is dissolved in the solution and 250 ⁇ g of IL-2 are added thereto. The final volume of the solution is brought to 10 ml with distilled water for injection.
  • Composition (A) is not practical because IL-2 became nearly insoluble in the course of the procedure outlined above.
  • compositions (B), (C), and (D) were prepared in order to elucidate how the final pH value of the solution influences the appearance of the reconstituted solution of a freeze-dried composition.
  • compositions (C) and (D) Compositions (C) and (D)
  • freeze-dried compositions (C) and (D) are prepared by freeze-drying the solutions adjusted to a pH of about 5.0 and about 5.6, respectively.
  • the item “Appearance” indicates any change observed in appearance of the freeze-dried compositions such as coloring, shrinking, caking, or the like; and "Turbidity when reconstituted” indicates any change observed in the appearance of the solutions of said compositions dissolved in 1 ml each of distilled water for injection.
  • the Item “% Activity” means the remaining activity (%) when IL-2 activity of the freeze-dried compositions just prepared is regarded as 100%.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Zoology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
EP87100067A 1986-01-07 1987-01-05 Interleukin-2 compositions Expired - Lifetime EP0229016B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT87100067T ATE82857T1 (de) 1986-01-07 1987-01-05 Interleukin-2-zusammensetzungen.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP1846/86 1986-01-07
JP61001846A JPH0645551B2 (ja) 1986-01-07 1986-01-07 インタ−ロイキン−２組成物

Publications (3)

Publication Number Publication Date
EP0229016A2 EP0229016A2 (en) 1987-07-15
EP0229016A3 EP0229016A3 (en) 1988-10-05
EP0229016B1 true EP0229016B1 (en) 1992-12-02

Family

ID=11512913

Family Applications (1)

Application Number Title Priority Date Filing Date
EP87100067A Expired - Lifetime EP0229016B1 (en) 1986-01-07 1987-01-05 Interleukin-2 compositions

Country Status (8)

Country Link
EP (1) EP0229016B1 (da)
JP (1) JPH0645551B2 (da)
KR (1) KR960012064B1 (da)
AT (1) ATE82857T1 (da)
CA (1) CA1288340C (da)
DE (2) DE229016T1 (da)
ES (1) ES2043609T3 (da)
GR (1) GR3006807T3 (da)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7847079B2 (en) 2001-12-21 2010-12-07 Human Genome Sciences, Inc. Albumin fusion proteins

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4992271A (en) * 1982-09-23 1991-02-12 Cetus Corporation Formulation for lipophilic IL-2 proteins
DE3621828A1 (de) * 1986-06-28 1988-01-14 Biotest Pharma Gmbh Stabilisierung eines fuer therapeutische zwecke, insbesondere beim menschen, bestimmten interleukin-2-praeparates sowie dieses praeparat enthaltende stabilisierte waessrige loesung oder feststoff
US5037644A (en) * 1986-10-27 1991-08-06 Cetus Corporation Pharmaceutical compositions of recombinant interleukin-2 and formulation processes
EP0284249A1 (en) * 1987-03-13 1988-09-28 Interferon Sciences, Inc. Lyophilized lymphokine composition
JPH0676332B2 (ja) * 1988-03-09 1994-09-28 大塚製薬株式会社 インターロイキン‐１βの安定化組成物
JP2799483B2 (ja) * 1988-03-09 1998-09-17 大塚製薬株式会社 インターロイキン−１β組成物の安定化方法
US5078997A (en) * 1988-07-13 1992-01-07 Cetus Corporation Pharmaceutical composition for interleukin-2 containing physiologically compatible stabilizers
ZA902663B (en) * 1989-04-07 1991-12-24 Syntex Inc Interleukin-1 formulation
JP2818834B2 (ja) * 1991-08-12 1998-10-30 大塚製薬株式会社 ＩＬ−１α安定化医薬製剤
FR2684878B1 (fr) * 1991-12-12 1994-02-11 Roussel Uclaf Composition pharmaceutique stabilisee d'il2 humaine recombinante non glycosylee sous forme reduite et son procede de preparation.
JP3098544B2 (ja) * 1994-05-06 2000-10-16 鐘紡株式会社 サイトカイン活性増強剤およびサイトカインの働きが低下した疾病の治療剤
WO1999018119A1 (fr) * 1997-10-03 1999-04-15 Shionogi & Co., Ltd. Procede de lyophilisation de proteines
EP1220682B1 (en) * 1999-10-04 2006-11-22 Novartis Vaccines and Diagnostics, Inc. Stabilized liquid polypeptide-containing pharmaceutical compositions
US6689353B1 (en) * 2000-06-28 2004-02-10 Bayer Pharmaceuticals Corporation Stabilized interleukin 2
SI1599222T1 (sl) 2003-01-08 2009-08-31 Novartis Vaccines & Diagnostic Stabilizirani vodni sestavki, ki obsegajo inhibitor poti tkivnega faktorja (TFPI) ali varianto inhibitorja poti tkivnega faktorja
DE10348550A1 (de) * 2003-10-20 2005-06-16 Hexal Biotech Forschungsgmbh Stabile wässrige G-CSF-haltige Zusammensetzungen
CN101837119B (zh) * 2010-05-19 2012-07-04 山东东阿阿胶股份有限公司 白介素-11半成品溶液的制备方法及其产品

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4462940A (en) * 1982-09-23 1984-07-31 Cetus Corporation Process for the recovery of human β-interferon-like polypeptides
JPS61500790A (ja) * 1984-03-28 1986-04-24 シタス　コ−ポレイシヨン 微生物的に製造されたインターロイキン―２を含有する組成物
EP0158487B1 (en) * 1984-04-09 1991-08-28 Takeda Chemical Industries, Ltd. Stable composition of interleukin-2
JPS60222424A (ja) * 1985-01-25 1985-11-07 Takeda Chem Ind Ltd インタ−ロイキン−２組成物
US4816440A (en) * 1985-09-26 1989-03-28 Cetus Corporation Stable formulation of biologically active proteins for parenteral injection

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7847079B2 (en) 2001-12-21 2010-12-07 Human Genome Sciences, Inc. Albumin fusion proteins
US8071539B2 (en) 2001-12-21 2011-12-06 Human Genome Sciences, Inc. Albumin fusion proteins
US8252739B2 (en) 2001-12-21 2012-08-28 Human Genome Sciences, Inc. Albumin fusion proteins
US8513189B2 (en) 2001-12-21 2013-08-20 Human Genome Sciences, Inc. Albumin fusion proteins
US8993517B2 (en) 2001-12-21 2015-03-31 Human Genome Sciences, Inc. Albumin fusion proteins
US9221896B2 (en) 2001-12-21 2015-12-29 Human Genome Sciences, Inc. Albumin fusion proteins
US9296809B2 (en) 2001-12-21 2016-03-29 Human Genome Sciences, Inc. Albumin fusion proteins

Also Published As

Publication number Publication date
JPS62164631A (ja) 1987-07-21
GR3006807T3 (da) 1993-06-30
DE229016T1 (de) 1988-01-14
KR870006901A (ko) 1987-08-13
KR960012064B1 (ko) 1996-09-12
ATE82857T1 (de) 1992-12-15
CA1288340C (en) 1991-09-03
DE3782828D1 (de) 1993-01-14
ES2043609T3 (es) 1994-01-01
DE3782828T2 (de) 1993-04-29
JPH0645551B2 (ja) 1994-06-15
EP0229016A3 (en) 1988-10-05
EP0229016A2 (en) 1987-07-15

Similar Documents

Publication Publication Date Title
EP0229016B1 (en) Interleukin-2 compositions
EP0820299B1 (en) Formulations for il-12
EP0735896B1 (en) Parathyroid hormone formulation
EP0082481B1 (en) Stabilised alpha-interferon formulations and their preparation
RU2091068C1 (ru) Способ получения консервированного, содержащего протеин человека, лекарственного средства для инъекционного или инфузионного введения
US5919443A (en) Stable lyophilized pharmaceutical preparations of G-CSF
Österberg et al. Development of a freeze-dried albumin-free formulation of recombinant factor VIII SQ
HU202761B (en) Process for producing stabilized erythropoietin compositions
EP1180368B1 (en) Freeze dried hgf preparations
EP0910399B1 (en) Stable pharmaceutical composition of bdnf
IL117405A (en) Stable preparations of transglutaminase and processes for their preparation
US4895716A (en) Stabilized formulations of gamma interferons
JP2006137678A (ja) インターロイキン−２組成物
CN1802171B (zh) 不包含血清白蛋白的人红细胞生成素的稳定水溶液
EP0420964A1 (en) Lyophilized peptide formulations
KR900004799B1 (ko) 안정한 감마 인터페론 제제 및 이의 제조방법
JP2010120966A (ja) 安定化されたタンパク組成物
EP0124018B1 (en) Pharmaceutical preparation containing purified fibronectin
KR880002037B1 (ko) 인터페론 조성물 및 이의 제조방법
JP2000198745A (ja) トロンボポイエチン組成物
EP3679925A1 (en) Pharmaceutical composition of docetaxel conjugate and preparation method
JPS62223129A (ja) インタ−ロイキン−２組成物
KR930004600B1 (ko) γ-인터페론 조성물의 제조방법
FI98601C (fi) Menetelmä glykosyloimattoman t-PA-johdannaisen K1K2P farmaseuttisen valmisteen valmistamiseksi
WO2022116134A1 (zh) 磷苯妥英钠固体组合物、冻干方法、及其用途

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH DE ES FR GB GR IT LI LU NL SE

TCNL Nl: translation of patent claims filed
ITCL It: translation for ep claims filed

Representative=s name: JACOBACCI CASETTA & PERANI S.P.A.

TCAT At: translation of patent claims filed
EL Fr: translation of claims filed
DET De: translation of patent claims
PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Kind code of ref document: A3

Designated state(s): AT BE CH DE ES FR GB GR IT LI LU NL SE

17P Request for examination filed

Effective date: 19890329

17Q First examination report despatched

Effective date: 19890824

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE ES FR GB GR IT LI LU NL SE

REF Corresponds to:

Ref document number: 82857

Country of ref document: AT

Date of ref document: 19921215

Kind code of ref document: T

ITF It: translation for a ep patent filed

Owner name: JACOBACCI & PERANI S.P.A.

RAP2 Party data changed (patent owner data changed or rights of a patent transferred)

Owner name: BIOGEN, INC.

Owner name: SHIONOGI SEIYAKU KABUSHIKI KAISHA

REF Corresponds to:

Ref document number: 3782828

Country of ref document: DE

Date of ref document: 19930114

ET Fr: translation filed
REG Reference to a national code

Ref country code: GR

Ref legal event code: FG4A

Free format text: 3006807

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2043609

Country of ref document: ES

Kind code of ref document: T3

EPTA Lu: last paid annual fee
EAL Se: european patent in force in sweden

Ref document number: 87100067.5

REG Reference to a national code

Ref country code: GB

Ref legal event code: IF02

REG Reference to a national code

Ref country code: CH

Ref legal event code: PUE

Owner name: BIOGEN IDEC MA INC.

Free format text: SHIONOGI SEIYAKU KK#12, DOSHO-MACHI, 3-CHOME#HIGASHI-KU/OSAKA-SHI/OSAKA (JP) $ BIOGEN, INC.#14 CAMBRIDGE CENTER#CAMBRIDGE/MA (US) -TRANSFER TO- BIOGEN IDEC MA INC.#14 CAMBRIDGE CENTER#CAMBRIDGE, MA 02142 (US)

REG Reference to a national code

Ref country code: FR

Ref legal event code: TP

Ref country code: FR

Ref legal event code: CD

BECA Be: change of holder's address

Owner name: *BIOGEN IDEC MA INC.14 CAMBRIDGE CENTER, CAMBRIDGE

Effective date: 20040826

BECH Be: change of holder

Owner name: *BIOGEN IDEC MA INC.14 CAMBRIDGE CENTER, CAMBRIDGE

Effective date: 20040826

NLS Nl: assignments of ep-patents

Owner name: BIOGEN IDEC MA INC.

NLT1 Nl: modifications of names registered in virtue of documents presented to the patent office pursuant to art. 16 a, paragraph 1

Owner name: BIOGEN IDEC MA INC.

Owner name: SHIONOGI SEIYAKU KABUSHIKI KAISHA

REG Reference to a national code

Ref country code: GB

Ref legal event code: 732E

REG Reference to a national code

Ref country code: ES

Ref legal event code: PC2A

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20051216

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20051221

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20051229

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20060117

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20060125

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20060126

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 20060127

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20060131

Year of fee payment: 20

Ref country code: IT

Payment date: 20060131

Year of fee payment: 20

Ref country code: GR

Payment date: 20060131

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20060215

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20060228

Year of fee payment: 20

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20070104

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20070105

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20070108

REG Reference to a national code

Ref country code: GB

Ref legal event code: PE20

NLV7 Nl: ceased due to reaching the maximum lifetime of a patent

Effective date: 20070105

EUG Se: european patent has lapsed
REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20070108

BE20 Be: patent expired

Owner name: *BIOGEN IDEC MA INC.

Effective date: 20070105